Prevention of Breast Cancer by Haploinsufficiency of RALBP1
Abstract
Objective: To determine whether chronic partial suppression of Rlip will prevent breast cancer through inhibition of epigenetic remodeling of genes necessary to transform pre-cancerous to cancerous cells. Rationale: p53 is a powerful tumor suppressor protein genetically damaged in about one-third of human breast cancers. Normally, p53 is activated by cancer-inducing oxidative stress. p53 deficiency destabilizes the genome, strongly promoting cancer. The uniform susceptibility to cancer of p53-deficient mice has never been suppressed as effectively as we show with Rlip depletion. Importantly, Rlip deficiency also lowered blood glucose, cholesterol, and triglycerides. Our findings are significant because they have unearthed a previously completely unknown mechanism by which p53 loss promotes cancer. The exact underlying mechanism for the potent cancer suppressive effect of Rlip deficiency is unknown, but our genomic studies have predicted a small set of genes that could be essential for the transformation of pre-cancerous to cancerous cells. We hypothesize that drugs that deplete or inhibit Rlip will exert potent breast cancer preventative and anti-metabolic syndrome effects. Ultimate applicability: Primary or secondary prevention as well as treatment of breast cancer. Which overarching challenge(s) does this research address? (1) Prevent breast cancer (primary prevention). (2) Identify what drives breast cancer growth and determine how to stop it. What types of patients will it help, and how will it help them? Rlip inhibitors could prevent breast cancer related to obesity or p53 dysfunction and could be used to treat women who already have breast cancer. Because the anticancer effects of Rlip are independent of ER status, the benefits would extend to triple-negative breast cancer. What are the potential clinical applications, benefits, and risks? Benefits include primary, secondary, and tertiary prevention of breast cancer with concurrent reduction of cardiovascular risk factors. Risks of adverse effects are likely to be minimal. Rlip deficiency has proven to cause no significant toxicity in over 300 treated mice across 8 published studies. What is the projected time it may take to achieve a patient-related outcome? As part of these studies, we will quantify the Rlip-depleting and cancer preventative effects of natural products that can inhibit or deplete Rlip. Because these can be readily formulated into drugs, the time to deployment is expected to be short, perhaps less than 3 years. What is the likely impact of this study on ending breast cancer? Because Rlip deficiency can block cancer susceptibility conferred by loss of the most powerful known tumor suppressor gene and could reduce the risk of breast cancer conferred by obesity, development of strategies to induce Rlip deficiency could be a major step towards eradiation of breast cancer. If the research is too basic for clinical applicability, describe the interim outcomes. We will understand new p53-Rlip related cancer mechanisms useful for design of clinical trials testing novel combinations of existing drugs based on knowledge about previously unknown mechanisms.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810534
Entities
People
- Sanjay Awasthi
Organizations
- Texas Tech University Health Sciences Center
- United States Army